カプトプリル 化學(xué)特性,用途語,生産方法
外観
白色～わずかにうすい褐色、結(jié)晶～粉末
溶解性
メタノールに極めて溶けやすく、エタノール(99.5)に溶けやすく、水にやや溶けやすい。
用途
アンジオテンシン変換酵素 （ACE-1）阻害剤です。アンジオテンシン変 換酵素を阻害し、アンジオテンシンⅡ生成抑 制作用を示します。
用途
カプトプリル（Captopril）とはアンジオテンシン変換酵素阻害薬の一つである。アンジオテンシン変換酵素（ACE）を抑制することにより血圧を低下させる。さらにアルドステロン分泌の抑制による利尿作用を有する。高血圧、うっ血性心不全の治療に使用される。カプトプリルは初のACE阻害薬であり、新規(guī)作用機序ならびに新規(guī)開発手法の2つの意味で革新的と云われる。
効能
血圧降下薬, アンジオテンシン変換酵素(ACE)阻害薬
商品名
カプトリル (第一三共エスファ); カプトリル (第一三共エスファ)
確認試験
本品につき，赤外吸収スペクトル測定法の
臭化カリウム錠剤法により試験を行い，本品のスペクトルと
本品の參照スペクトルを比較するとき，両者のスペクトルは
同一波數(shù)のところに同様の強度の吸収を認める．
貯法
容器 気密容器．
乾燥減量
0.30％以下(1g，減圧，シリカゲル，4時間)．
強熱殘分
0.1％以下(1g)．
説明
Captopril is the most studied of the angiotensin-converting enzyme inhibitors proposed as an
antihypertensive drug. It blocks angiotensin-converting enzyme, which suppresses formation
of angiotensin II and relieves its vasoconstricting effect on arterial and venous vessels. Overall
vascular peripheral tension is reduced, which results in the lowering of arterial pressure.
化學(xué)的特性
White or almost white, crystalline powder.
使用
Captopril has also been shown to inhibit the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density. Captopril demonstrates noncompetitive inhibition of tyrosinase monophenolase activity and competitive inhibition of diphenolase activity
定義
ChEBI: A L-proline derivative in which L-proline is substituted on nitrogen with a (2S)-2-methyl-3-sulfanylpropanoyl group. It is used as an anti-hypertensive ACE inhibitor drug.
生物學(xué)の機能
Captopril (Capoten) is an orally effective ACE inhibitor
with a sulfhydryl moiety that is used in binding to the
active site of the enzyme. Captopril blocks the blood
pressure responses caused by the administration of angiotensin
I and decreases plasma and tissue levels of angiotensin
II.
一般的な説明
Captopril, 1-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]proline (Capoten), blocks the conversion of angiotensinI to angiotensin II by inhibiting the convertingenzyme. The rational development of captopril as an inhibitorof ACE was based on the hypothesis that ACE and carboxypeptidaseA functioned by similar mechanisms. It wasnoted that d-2-benzylsuccinic acid was a potent inhibitor ofcarboxypeptidase A, but not ACE. By use of this small molecule as a prototype, captopril was designed with a carboxylgroup on a proline and a thiol group was introduced toenhance the binding to the zinc ion of ACE. The importantbinding points at the active site of ACE are thought to be anarginine residue, which provides a cationic site that attracts acarboxylate ion, and a zinc ion, which can polarize a carbonylgroup of an amide function to make it more susceptible to hydrolysis.Hydrophobic pockets lie between these groups in theactive site, as does a functional group that forms a hydrogenbond with an amide carbonyl.
副作用
Approximately 10% of the patients treated with
captopril report a dose-related maculopapular rash
that often disappears when the dosage of captopril is
reduced. Other common adverse effects are fever, a
persistent dry cough (incidence as high as 39%), initial
dose hypotension, and a loss of taste that may result in
anorexia. These effects are reversed when drug therapy
is discontinued. More serious toxicities include a
1% incidence of proteinuria and glomerulonephritis;
less common are leukopenia and agranulocytosis.
Since food reduces the bioavailability of captopril by
30 to 40%, administration of the drug an hour before
meals is recommended. All converting enzyme inhibitors
are contraindicated in patients with bilateral
renal artery disease or with unilateral renal artery disease
and one kidney. Use under these circumstances
may result in renal failure or paradoxical malignant
hypertension.
代謝
The onset of action following oral administration of
captopril is about 15 minutes, with peak blood levels
achieved in 30 to 60 minutes. Its apparent biological
half-life is approximately 2 hours, with its antihypertensive
effects observed for 6 to 10 hours. The kidneys appear
to play a major role in the inactivation of captopril.
純化方法
Purify it by recrystallisation from EtOAc/hexane. It is also purified by dissolving in EtOAc and chromatographed on a column of Wakogel C200 using a linear gradient of MeOH in EtOAc (0-100o) and fractions which give a positive nitroprusside test (for SH), are combined, evaporated and recrystallised from EtOAc/hexane (1:1), to give white crystals with [] D -128.2o (c 2.0, EtOH). [Nam J Pharm Sci 73 1843 1984]. Alternatively, dissolve it in H2O, apply to a column of AG-50Wx2 (BioRad) and elute with H2O. The free acid is converted to the dicyclohexylamine salt in MeCN by addition of the amine until the pH is 8-9. The salt is converted to the free acid by shaking with EtOAc and 10% aqueous KHSO4 or passage through an AG50Wx2 column. The EtOAc solution is dried (MgSO4), evaporated to dryness and the residue is recrystallised as above from EtOAc/hexane [Cushman et al. Biochemistry 16 5484 1977, NMR and IR: Horii & Watanabe Yakugaku Zasshi (J Pharm Soc Japan) 81 1786 1961]. It is an antihypertensive because it is a potent competitive inhibitor of the angiotensive convertive enzyme (ACE-inhibitor) with a Ki value of 0.0017\M [Shimazaki et al. Chem Pharm Bull Jpn 30 3139 1982].
カプトプリル 上流と下流の製品情報
原材料
準備製品